Adamantyl azidoformates



United States Patent 3,470,210 ADAMANTYL AZIDOFORMATES Koert Gerzon andEriks V. Krumkalns, Indianapolis, Ind., assignors to Eli Lilly andCompany, Indianapolis, Ind., a corporation of Indiana No Drawing.Original application Jan. 21, 1965, Ser. No. 427,124, now Patent No.3,345,399, dated Oct. 3, 1967. Divided and this application Feb. 13,1967, Ser. No.

Int. Cl. C07d 109/00, 27/04 US. Cl. 260-349 1 Claim ABSTRACT OF THEDISCLOSURE The preparation of adamantyl azidoformates, useful asintermediates, is described.

CROSS-REFERENCE This application is a division of our earlierapplication, Ser. No. 427,124, filed Ian. 21, 1965, now US. Patent No.3,345,399, issued Oct. 3, 1967.

BACKGROUND OF THE INVENTION Adamantane was first isolated from petroleumby Landa and Machacek in 1933 [S. Landa and V. Machacek, Coll. Czech.Chem. Comm., 5, l (1933)]. Adamantame and alkylated adamantanes are nowprepared by various synthetic procedures as outlined in Chem. Reviews,64, 277 (1964). The above article also discusses the preparation ofderivatives of adamantane; for example, adamantoic acid, adamantylamine,adamantyl chloride and adamantyl alcohol. Various esters and amides ofadamantoic acid as well as adamantoyl chloride are described, but only afew derivatives of adamantyl alcohol.

SUMMARY OF THE INVENTION The compounds provided by this invention can berepresented by the following formulas:

wherein AD is a member of the group consisting of adamantyl,methyladamantyl, dimethyladamantyl and homo-adamantyl; R is a member ofthe group consisting of hydrogen, C -C alkyl, hydroxy-substituted C -Calkyl, carboxy lower alkyl-substituted C C, alkyl, mercapto-substitutedC -C alkyl, lower alkyl-mercapto-substituted C -C alkyl,guanidino-substituted C -C alkyl, benzyl, substituted benzyl,imidazolylmethyl, indolymethyl, hydroxyindolylmethyl, phenyl,substituted phenyl, thienyl, and furyl; R is a member of the groupconsisting of hydrogen and C -C alkyl; and R is a member of the groupconsisting of hydrogen and hydroxyl. Also included within the scope ofthis invention are alkali metal and amine salts of acids represented bythe above formulas.

Adamantane and homo-adamantane, from which are derived the adamantyl,methyladamantyl, dimethyladamantyl and homo-adamantyl radicals referredto above, are tricyclic multi-bridged hydrocarbons. Their structures3,470,210 Patented Sept. 30, 1969 "ice are conventionally represented intwo dimensions by the following formulas:

adamantane homo-adamantane As can be seen from the above formulas, inadamantane, all oddand all even-numbered positions are equivalent.Homo-adamantane has two pairs of equivalent bridgehead carbon atoms, Cand C and C and C In the above formula, when R or R is C -C alkyl, itcan be, illustratively, isobutyl, sec.-butyl, isopropyl, npropyl,methyl, ethyl, n-butyl and t-butyl. When R is a substituted C -C alkylgroup, said substituents being mercapto, lower alkyl mercapto, carboxylower alkyl, guanidino, and hydroxy, illustrative radicals which R canrepresent include hydroxymethyl, mercaptomethyl, methylmercaptomethyl,methylmercaptoethyl, ethylmerpactomethyl, 'y-guanidinobutyl,B-hydroxyethyl, B-hydroxy-tbutyl, fl-isopropylmercaptoethyl,'y-hydroxypropyl, 'y-mercapto-n-butyl, carboxymethyl, fl-carboxyethyl,and the like. The term lower alkyl as used herein means an alkyl grouphaving from 1 to 3 carbon atoms, and includes methyl, ethyl, n-propyland isopropyl. When R represents a substituted-benzyl group orsubstituted-phenyl group, the substituents in the phenyl ring can behalo such as fluoro, chloro, bromo, iodo and the like; lower alkyl,lower alkoxy, hydroxy, and halo-substituted lower alkyl. Thus, groupswhich illustrate R when it is a substitutedbenzyl or substituted-phenylradical include 3,5-di-iodo-4- hydroxybenzyl, 3,4-dihydroxybenzyl,4-hydroxybenzyl, 4- trifluoromethylbenzyl, 4-trichloromethylbenzyl,4-pentafluoroethylbenzyl, 4-a-bromopropylbenzyl, veratryl, isovanillyl,vanillyl, 4-isopropoxybenzyl, 2,4-dimethylbenzyl, 3-isopropylbenzy1,4-chlorophenyl, 2,6-dibromophenyl, m-tolyl, 3,4-xylyl, p-anisyl,p-propoxyphenyl, m-ethoxyphenyl, 4-iodophenyl,3,5-di-iodo-4hydroxyphenyl, ptrifluoromethylphenyl, and the like. Othersubstituents, in addition to those enumerated above, can be present inthe phenyl group or in the phenyl portion of the benzyl group withoutany qualitative change in the properties of the parent compound, as willbe apparent to those skilled in the art. When R is a hydroxy-substitutedindolylmethyl radical, the hydroxy group is in the benzo portion of theindolyl radical. R can then also be, illustratively,S-hydroxyindolylmethyl, 6-hydroxyindolylmethyl, and the like.

Illustrative compounds coming within the scope of this invention includethe following:

N-l-adamantyloxycarbonyl L-tyrosine N-3-methyladamantyloxycarbonylL-phenylalanine N,N-bis-(l-adamantyloxycarbonyl) L-cystineN-3,5-dimethyladamantyloxycarbonyl D-valine ethylN-3-homo-adamantyloxycarbonyl 2,4-dichlorophenylalaninateN-l-adamantyloxycarbonyl 2, 6-dimethoxyphenylglycineN-l-adamantyloxycarbonyl L-proline.

As can readily be seen, compounds represented by the above formulasinclude the N-adamantyloxycarbonyl derivatives of all the naturallyoccurring tic-amino acids, as well as lower homologues and isosteresthereof. These compounds are all unseful in the synthesis of peptides,both natural and unnatural, inasmuch as the adamantyloxycarbonyl groupcan act as a blocking group by preventing both the reaction of theblocked amino group with an acylating agent and the formation of azwitterion.

When employed as a blocking group in peptide synthesis, theadamantyloxycarbonyl group has the advantage of yielding more stablederivatives than are obtained with conventional blocking .groups, yetwhich are at the same time readily hydrolizable under conditionsordinarily used to remove the conventional blocking groups. In addition,the N-adamantyloxycarbonyl derivatives of amino acids, as represented bythe above formulas, can be used in the synthesis of penicillins andcephalosporins. In such reactions, the adamantyloxycarbonyl group againfunctions as a blocking group, preventing not only reaction of the aminofunction with cephalosporanic acid or penicillanic acid or with itself,but also formation of an unreactive zwitterion. The ease of splittingthe adamantyloxycarbonyl group from the resulting penicillin orcephalosporin prevents any undue destruction of the penicillin orcephalosporin necessitated by the use of more acidic hydrolyticreagents.

In addition to their case of hydrolysis, the adamantyloxycarbonylderivatives of amino acids are more easily isolated than thecorresponding compounds using more conventional blocking groups.Furthermore, the adamantylcarbamates themselves are frequentlycrystalline, in contrast to derivatives of amino acids with the moreconventional blocking agents.

The adamantyloxycarbonyl blocking group can be readily cleaved from theadamantylcarbamate by treatment with trifluoroacetic acid or withanhydrous hydrogen chloride in an inert solvent such as dioxane. OtherREACTION SEQUENCE I pyridine o=( JoAD wherein AD, R, R and R have thesame meaning as hereinabove. In carrying out the above reactionsequence, l-hydroxyadamantane or 3-methyl-l-hydroxyadamantane or 3,S-dimethyl-l-hydroxyadamantane or 3-hydroxyhomo-adamantane is reactedwith phosgene in the presence of a tertiary amine such as pyridine,trimethylpyridine, quinoline, or tri-ethylamine in an inert solvent,such as anhydrous benzene or ether or other hydrocarbon or etherealsolvents, to form the corresponding adamantyl chloroformate. It wascompletely unexpected that the chloroformates of adamantane and itscongeners would be stable inasmuch as t-butylchloroformate, the openchain analog of these compounds, is completely unstable and cannot beisolated, according to Choppin and Rogers, I. Am. Chem. Soc., 70, 2967(1948). The instability of t-butylchloroformate was to be expected fromits presumed readiness to form the transient t-butylcarbonium ion whichdisappears rapidly in solution to yield either the corresponding alcoholor chloride or to yield isobutene, depending upon the physical andchemical environment. No theoretical reason is known why the adamantylchloroformates do not also spontaneously decompose to yield thecorresponding carbonium ions and then disappear as the hydroxy compoundor the chloride or as tar (inasmuch as an unsaturated compoundcorresponding to isobutene cannot be formed from thel-adamantylcarbonium ion). Not only are these adamantyl chloroformatessufficiently stable to enable the compound to be used in furtherreactions such as the formation of adamantyloxycarbonyl derivatives, butalso, in the case of l-adamantyl chloroformate itself, for example, thecompound can be isolated as a white crystalline solid with a meltingpoint well above ordinary room temperature.

Inasmuch as the adamantyl chloroformates are reasonably stable at 0 C.,the second step of the reaction, the formation of theN-adamantyloxycarbonyl derivative of the amino acid, takes place readilyand in good yield by simply mixing the two reactants in an inertsolvent, under slightly alkaline conditions. In order to have suchalkaline conditions, we prefer to employ the sodium salt of the aminoacid as the starting material and to add dilute sodium hydroxide or itsequivalent as required in dropwise fashion during the course of thereaction. Useful inert solvents include ethers, such as dioxane orether, alcohols, such .as t-butanol or ethanol, and mixtures of thesesolvents with water.

An alternative and somewhat more complex route starting with adamantylchloroformate is available for the preparation of the compounds of thisinvention and is outlined in Reaction Sequence II below.

REACTION SEQUENCE II wherein AD, R, R and R" have the same meaning ashereinabove. According to the above reaction sequence, an N-adamantylchloroformate is reacted with hydrazine to yield the correspondingl-adamantyl or 3-methyll-adamantyl or 3, S-dimethyl-l-adamantyl or3-homoadamantyl carbazate. Reaction of the carbazate with nitrous acidyields the corresponding azidoformate, which compound reacts with theu-amino acid to yield an N- adamantyloxycarbonyl derivative of the aminoacid in good yield. The adamantyl carbazates,

can also be prepared by reacting an adamantyl-p-nitrophenyl carbonatewith anhydrous hydrazine or by reacting an O-l-adamantyl-S-methylthiolcarbonate with anhydrous hydrazine.

Although, as indicated above, an adamantyl azidoformate can react withan amino acid to yield the same derivative as would be obtained byreaction of the amino acid with an adamantyl chloroformate, there is aconsiderable advantage to using the chloroformate in place of theazidoformate. The latter type of compound is potentially explosive, andit is a considerable advantage of this invention that, in the adamatylseries, it is possible to use the virtually non-explosive, yet morereactive, chloroformate as a blocking group in peptide synthesis.

As is apparent from Reaction Sequences I and II, the adamantylchloroformates are useful as intermediates in various reactions. It isalso apparent from Reaction Sequence II that the carbazates andazidoformates of adamantane, 3-methyladamantane, 3,5-dimethyladamantaneand homo-adamantane, are also useful as intermediates in the synthesisof the compounds of this invention.

This invention is further illustrated by the following specificexamples:

EXAMPLE I l-hydroxyadamantane from l-bromoadamantane A reaction mixturecontaining 21 g. of l-bromoadamantane, 50 ml. of 85% hydrazine hydrate,and 150 ml. of ethanol was heated to refluxing temperature for abouthours. Removal of the volatile constitutents by evaporation in vacuoyielded a solid residue comprising l-hydroxyadamantane. The residue wastreated with 100 ml. of cold water and the l-hydroxyadamantane taken upin 500 ml. of ether. The ether extract was separated and dried, and theether removed by evaporation in vacuo. The resulting residue weighing12.6 g. and melting at 220 C., was found to be identical in all respectsto l-hydroxyadamantane as prepared by Stetter, Ber., 92, 1679 (1959).

EXAMPLE II l-adamantyl chloroformate A solution containing g. ofphosgene in 100 ml. of anhydrous benzene was maintained at about 20 C.by means of an ice-water bath. A mixture containing 8 g. ofl-hydroxyadamantane, 6 g. of pyridine, and 200 ml. of ether was addeddropwise with stirring to the phosgene solution over a period of about 1hour while still maintaining the solution temperature at about 20 C.During the addition, a white solid precipitate was formed, and anadditional 100 ml. of anhydrous benzene were added to give a betterdispersion of the solids in the reaction mixture. After the addition hadbeen completed, the reaction mixture was maintained at ambienttemperature for about 1 hour and was then filtered. The filtrate waspoured over a mixture of ice and water, and this mixture was then placedin a separatory funnel and shaken. The organic layer was separated anddried, and its volume reduced by about 80% by evaporation in vacuo. Analiquot of the resulting solution was evaporated in vacuo to dryness atroom temperature, yielding l-adamantyl chloroformate as a whitecrystalline solid melting at about 40-42 C. Recrystallization wasachieved from anhydrous petroleumether (boiling point=30-60 C.) at 20C., yielding crystals melting at about 46-47 C. Infrared spectrum of theproduct confirmed the expected structure.

Analysis.Calc.: C, 61.54; H, 7.04; Cl, 16.52. Found: C, 61.48; H, 7.06;Cl, 16.93.

Adamantyl chloroformate can be stored essentially without decompositionat 4 C. in benzene-ether solution by addition of a small amount ofcalcium carbonate as a stabilizer.

EXAMPLE III 3,5-dimethyl-1-adamantyl chloroformate Following theprocedure of Example II, 3,5-dimethyll-hydroxyadamantane was reactedwith phosgene in benzene solution in the presence of pyridine. Thecompound was isolated and purified by the procedures of the same exampleand had the typical infrared absorption spectrum characteristic ofoxycarbonyl chlorides; M.P.'=about 5l0 C.

EXAMPLE IV 3-homo-adamantyl chloroformate 3-homo-adamantyl chloroformatewas prepared by the procedure of Example II from phosgene and3-hydroxyhomo-adamantane. This latter compound was prepared by theprocedure of Stetter and Goebel, Ber., 96, 550 (1963). The compound wasisolated in crystalline form from petroleum-ether at 50" C., but itsmelting point was below 0 C. The liquid had the typical infraredabsorption spectrum characteristic of oxycarbonyl chlorides.

6 EXAMPLE v l-adamantyl carbamate l-adamantyl chloroformate was furthercharacterized by its conversion to the corresponding carbamate asfollows:

A solution of 75 mg. of l-adamantyl chloroformate in 25 ml. of anhydrousbenzene was saturated with gaseous ammonia for about 1 hour. Thereaction flask was then stoppered, and the resulting solution maintainedat ambient temperature for 24 hours. The reaction mixture was thenfiltered, and the filtrate shaken with 200 ml. of an ice-water mixture.Two hundred milliliters of ether were added, and the ether-benzene layerwas separated and dried. Evaporation of the resulting solution in vacuoyielded l-adamantyl carbamate, which melted at about 170-171 C. afterrecrystallization from boiling anhydrous ethanol.

Analysis.-Calc.: N, 7.25. Found: N, 6.83.

l-adamantyl carbamate prepared as above was found to be identical tol-adamantyl carbamate prepared by the interaction at elevatedtemperature of ammonia and adamantyl phenylcarbonate, prepared by thegeneral method for preparation of phenylcarbamates given by McLamore, J.Org. Chem., 20, 1379 (1955).

l-adamantyl N-methyl carbamate was prepared by the above procedure bysubstituting methylamine for ammonia. l-adamantyl N-methyl carbamatethus prepared melted at about 127-129 C. on recrystallization from anether-hexane solvent mixture.

Analysis.--Calc.: C, 68.86; H, 9.15; N, 6.69. Found: C, 68.51; H, 9.04;N, 6.77.

EXAMPLE VI l-adamantyl N-adarnantyl carbamate l-adamantyl chloroformatewas also characterized by conversion to the N-adamantyl carbamate byreaction with adamantylamine as follows:

A solution containing 0.3 g. of l-adamantyl chloroformate dissolved in12.5 ml. of anhydrous ether was added to a stirred solution containing 1g. of adamantylamine in 25 ml. of anhydrous ether in dropwise fashion atroom temperature. After the addition had been completed, stirring wascontinued for an extra half hour. Adamantylamine hydrochloride, aby-product of the reaction forming l-adamantyl N-adamantyl carbamate,was removed by filtration. The filtrate was washed twice with 5-ml.portions of 1 N aqueous hydrochloric acid and twice with water to removethe excess adamantylamine. The filtrate was then dried and concentratedby heating at atmospheric pressure. Pentane was then added to the heatedsolution to the point of incipient precipitation, and the solution wascooled, yielding l-adamantyl N-adamantyl carbamate, melting at about305-310 C.

Analysis.Calc.: C, 76.55; H, 9.48; N, 4.25. Found: C, 76.65; H, 9.68; N,4.09.

The adamantyl carbamates are useful as insecticides.

EXAMPLE VII l-adamantyl azidoformate Forty milligrams of sodium nitritecrystals were added to a mixture of mg. of l-adamantyl carbazate, 1 ml.of 2 N aqueous hydrochloric acid and 2 ml. of acetone. The mixture wasshaken until the crystals had dissolved. Two milliliters of wate wereadded. A water-insoluble yellow oil was obtained and was extracted withthree 25-ml. portions of hexane. The hexane extracts were combined andwashed with 10% hydrochloric acid, 10% sodium bicarbonate solution, andwater. The hexane solution was then separated and dried. Evaporation ofthe hexane in vacuo yielded a pale yellow oily liquid which had thetypical infrared absorption spectrum of an acid azide.

If desired, the azidoformate can also be prepared utilizing otherstandard reagents, as for example, by the reaction of adammantylchloroformate and sodium azide.

EXAMPLE VIII l-adamantyl carbazate A solution containing 2 g. ofl-adamantyl chloroformate in 150 ml. of benzene was added slowly to awellstirred solution of 2.5 g. of anhydrous hydrazine in 20 ml. oft-butyl alcohol, After the reaction mixture had been stirred for abouttwo hours, the solvents were removed in vacuo. The sirupy residue wasdissolved in a mixture of 150 ml. of ether and 10 ml. of water. Theether layer was separated, washed with 35-ml. portions of water, with 5ml. of 1% sodium carbonate solution, and again with 5 ml. of water. Theethereal solution was dried. Ten milliliters of anhydrous hexane wereadded and the solution concentrated to a volume of about ml. Cooling thesolution at about 10 C. yielded shiny, White crystalline plates ofl-adamantyl carbazate melting at about AnaIysis.Calc.: N, 13.32. Found:N, 12.99.

l-adamantyl carbazate can also be prepared by the interaction ofl-adamantyl p-nitrophenyl carbonate and hydrazine. l-adamantylp-nitrophenyl carbonate itself is prepared from l-hydroxyadamantane bythe method of Anderson and McGregor, J. Am. Chem. Soc., 79, 6181 (1964).The carbonate melts at about 106-108 C. on recrystallization from ahexane-ether solvent mixture.

Analysis.-Calc.: C, 64.34; H, 6.04; N, 4.41. Found: C, 64.16; H, 5.81;N, 4.60.

l-adamantyl carbazate can also be prepared by heating O-I-adamantylS-methyl thiolcarbonate with hydrazine. O-l-adamantyl S-methylthiolcarbonate itself is prepared from l-hydroxyadamantane and methylchlorothioformate according to the general procedure described byCarpino, J. Org. Chem, 28, 1910 (1963).

3,5-dimethyl-1-adamantyl carbazate was prepared from3,5-dimethyl-1-adamantyl chloroformate and hydrazine according to theabove procedure. In addition, 1-homoadamantyl carbazate was preparedfrom l-homo-adamantyl chloroformate and hydrazine. Both of the abovecompounds gave the typical infrared carbazate spectrum, having thestrong absorption at 5.9 and 6.1;]. characteristic ofoxycarbonylhydrazides.

Following the above procedure, 3-homo-adamantyl chloroformate wasreacted with anhydrous hydrazine to yield the corresponding carbazatewhich melted at about 67 C.

Analysis.-Calc.: N, 12.41. Found: N, 11.97.

Following the above procedure, 3,5-dimethyl-l-adamantyl chloroformatewas reacted with anhydrous hydrazine to yield the correspondingcarbazate; M.P.=74- 75 C.

Analysis.-Calc.: N, 11.76. Found: N, 11.37.

S-methyl-l-adamantyl chloroformate and carbazate are prepared bysubstituting 3-methyl-1-adamantyl alcohol for the corresponding3,5-dimethyl compound employed in the above procedure.

EXAMPLE IX N-l-adamantyloxycarbonyl-D-phenylglycine A solution of sodiumD-phenylglycine was prepared by suspending 151 mg. of D-phenylglycine ina mixture of 2 ml. of water and 1.2 ml. of 1 N aqueous sodium hydroxideat 0 C. A second solution containing 225 mg. of l-adamantylchloroformate in a mixture of 2.5 ml. of dioxane and 1 ml. of ether wasadded in 5 portions to the sodium D-phenylglycinate solution over aperiod of about 40 minutes. During the addition of the acid chloridesolution, an additional 1 ml. of 1 N aqueous sodium hydroxide was addeddropwise in order to maintain a slightly alkaline pH in the reactionmixture. The reaction mixture was next extracted with three volumes ofether to remove any unreacted adamantyl chloroformate. The alkalineaqueous layer was cooled to about 0 C. and cautiously acidified withphopshoric acid until a pH of approximately 4.5 was attained. A milkyprecipitate of N 1 adamantyloxycarbonyl-D-phenylglycine formed and wasextracted with ether. The other solution was separated and dried.Evaporation of the ether in vacuo yielded an oily residue, triturationof which With a few drops of cyclohexane followed by refrigeration atabout 0 C. yielded N-l-adamantyloxycarbonyl-D-phenylglycine as a whitecrystalline solid weighing 228 mg. and melting at about 119-121 C.

Analysis.-Calc.: C, 69.28; H, 7.04; N, 4.25. Found: C, 69.22; H, 7.17;N, 4.18.

The above compound can also be prepared by the interaction ofl-adamantyl azidoformate and phenylglycine in the presence oftri-ethylamine. Furthermore, the same derivative can be prepared byreaction of the amino acid with l-adamantyl p-nitrophenyl carbonate orwith 0-1- adamantyl S-methyl thiolcarbonate.

EXAMPLE X N-l-adamantyloxycarbonyl glycine Following the procedure ofExample IX, l-adamantyl chloroformate was reacted with sodium glycinateto yield N-l-adamantyloxycarbonyl glycine melting at about 141- 142.5 C.after recrystallization from hexane.

Analysis.Calc.: N, 5.53. Found: N, 5.81.

In addition to the amino acids utilized in Example IX and X, thefollowing amino acids will also yield adamantyloxycarbonyl derivatives:leucine, isoleucine, tyrosine, valine, serine, alanine, phenylalanine,DOPA, norleucine, histidine, di-iodo tyrosine, arginine, cysteine,methionine, ethionine, proline, hydroxyproline, aspartic acid andglutamic acid.

We claim:

1. An adamantyl azidoformate of the formula wherein AD is a member ofthe group consisting of ladamantyl, 3 methyl l-adamantyl,3,5-dimethyl-1-adamantyl, and 3-homoadamantyl.

No references cited.

HENRY R. JILES, Primary Examiner C. M. SHURKO, Assistant Examiner

